1-201110216-G-C

Variant names:

• chr1-201110216-G-C
• rs12406479
• NM_000069.3:c.206C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000069.3(CACNA1S):​c.206C>G​(p.Ala69Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0464 in 1,614,088 control chromosomes in the GnomAD database, including 2,004 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A69D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.035 (135 hom., cov: 33)
  • Exomes 𝑓: 0.048 (1869 hom.)
• Consequence: CACNA1S NM_000069.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 7.65
• Publications: 25 publications found

Genes affected

CACNA1S (HGNC:1397): (calcium voltage-gated channel subunit alpha1 S) This gene encodes one of the five subunits of the slowly inactivating L-type voltage-dependent calcium channel in skeletal muscle cells. Mutations in this gene have been associated with hypokalemic periodic paralysis, thyrotoxic periodic paralysis and malignant hyperthermia susceptibility. [provided by RefSeq, Jul 2008]

CACNA1S Gene-Disease associations (from GenCC):

• hypokalemic periodic paralysis, type 1

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• malignant hyperthermia, susceptibility to, 5

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• congenital myopathy 18

  Inheritance: AR, AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• congenital myopathy

  Inheritance: SD, AD, AR Classification: STRONG Submitted by: Illumina, Genomics England PanelApp
• hypokalemic periodic paralysis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009147704).
• BP6: Variant 1-201110216-G-C is Benign according to our data. Variant chr1-201110216-G-C is described in ClinVar as Benign. ClinVar VariationId is 254811.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0502 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000069.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1S	NM_000069.3	MANE Select	c.206C>G	p.Ala69Gly	missense	Exon 2 of 44	NP_000060.2	Q13698

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CACNA1S	ENST00000362061.4	TSL:1 MANE Select	c.206C>G	p.Ala69Gly	missense	Exon 2 of 44	ENSP00000355192.3	Q13698
	CACNA1S	ENST00000367338.7	TSL:5	c.206C>G	p.Ala69Gly	missense	Exon 2 of 43	ENSP00000356307.3	B1ALM3
	CACNA1S	ENST00000681874.1		c.206C>G	p.Ala69Gly	missense	Exon 2 of 43	ENSP00000505162.1	A0A7P0T8M7

Frequencies

GnomAD3 genomes AF: 0.0350 AC: 5326 AN: 152216 Hom.: 134 Cov.: 33

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0375

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0391

Gnomad FIN AF: 0.0463

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0516

Gnomad OTH AF: 0.0397

GnomAD2 exomes AF: 0.0362 AC: 9110 AN: 251420 AF XY: 0.0383

Gnomad AFR exome AF: 0.00898

Gnomad AMR exome AF: 0.0200

Gnomad ASJ exome AF: 0.00973

Gnomad EAS exome AF: 0.000217

Gnomad FIN exome AF: 0.0439

Gnomad NFE exome AF: 0.0505

Gnomad OTH exome AF: 0.0349

GnomAD4 exome AF: 0.0476 AC: 69613 AN: 1461754 Hom.: 1869 Cov.: 33 AF XY: 0.0475 AC XY: 34522 AN XY: 727176

African (AFR) AF: 0.00777 AC: 260 AN: 33480

American (AMR) AF: 0.0203 AC: 908 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0105 AC: 275 AN: 26136

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39698

South Asian (SAS) AF: 0.0413 AC: 3563 AN: 86252

European-Finnish (FIN) AF: 0.0447 AC: 2388 AN: 53420

Middle Eastern (MID) AF: 0.0338 AC: 195 AN: 5768

European-Non Finnish (NFE) AF: 0.0535 AC: 59443 AN: 1111892

Other (OTH) AF: 0.0427 AC: 2577 AN: 60386

GnomAD4 genome AF: 0.0350 AC: 5326 AN: 152334 Hom.: 135 Cov.: 33 AF XY: 0.0344 AC XY: 2564 AN XY: 74484

African (AFR) AF: 0.0100 AC: 417 AN: 41594

American (AMR) AF: 0.0374 AC: 573 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0112 AC: 39 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.0396 AC: 191 AN: 4824

European-Finnish (FIN) AF: 0.0463 AC: 492 AN: 10622

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0516 AC: 3513 AN: 68020

Other (OTH) AF: 0.0393 AC: 83 AN: 2114

Alfa AF: 0.0450 Hom.: 123

Bravo AF: 0.0324

TwinsUK AF: 0.0556 AC: 206

ALSPAC AF: 0.0498 AC: 192

ESP6500AA AF: 0.0102 AC: 45

ESP6500EA AF: 0.0541 AC: 465

ExAC AF: 0.0372 AC: 4510

Asia WGS AF: 0.0140 AC: 47 AN: 3478

EpiCase AF: 0.0520

EpiControl AF: 0.0484

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Malignant hyperthermia, susceptibility to, 5 (3)
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Hypokalemic periodic paralysis, type 1 (2)
-	-	1	Congenital myopathy 18 (1)
-	-	1	Malignant hyperthermia, susceptibility to, 5;C3714580:Hypokalemic periodic paralysis, type 1 (1)
-	-	1	Thyrotoxic periodic paralysis, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.30
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0091	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.7
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.37
Sift	Benign	0.17	T
Sift4G	Benign	0.22	T
Polyphen		0.87	P
Vest4		0.26
MPC		0.40
ClinPred		0.026	T
GERP RS		4.9
Varity_R		0.34
gMVP		0.72
Mutation Taster		=69/31	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12406479; hg19: chr1-201079344; COSMIC: COSV62939394; COSMIC: COSV62939394;